Compositions for caries prophylaxis containing indium fluorogermanate in2(gef6)3



United States Patent 3,546,335 COMPOSITIONS FOR CARIES PROPHYLAXISCONTAINING INDIUM FLUOROGERMA- NATE In (GeF Joseph C. Muhler,Indianapolis, Ind., assignor to Indiana University Foundation,Bloomingtou, Ind., a not for profit corporation of Indiana No Drawing.Original application Jan. 15, 1968, Ser. No. 697,618. Divided and thisapplication July 16, 1969, Ser. No. 862,558

Int. Cl. A611 7/16 US. Cl. 424-52 10 Claims ABSTRACT OF THE DISCLOSURE Anew composition of matter comprising indium, germanium, and fluorine,namely, indium fluorogermanate, In (GeF has been discovered. Thiscompound when incorporated into oral compositions for caries prophylaxis(e.g., as a constituent of a dentifrice or prophylaxis paste) hasdemonstrated substantial utility as a topical anticariogenic agent.

CROSS REFERENCE This application is a division of applicants co-pendingapplication for United States patent, Ser. No. 697,618, filed Jan. 15,1968.

BACKGROUND OF THE INVENTION Field of the invention This inventionrelates to a new composition of matter, indium fluoroger-manate, In (GeFand to oral compositions for caries prophylaxis incorporating same. Bythe term oral composition is meant a product which in the ordinarycourse of usage is not intentionally ingested, but is retained in theoral cavity so as to contact the oral hard tissues. Such productsinclude, by way of example, dentifrices, mouthwashes, dental prophylaxispastes, and aqueous topical solutions.

Description of the prior art It is commonly recognized that the presenceof small (i.e. about 1.0 g/ml.) amounts of fluoride ion in drinkingwater has a significant effect in reducing the incidence of dentalcaries in humans. Sodium fluoride, as an example, has been introducedinto the public water supplies in a number of communities with goodresults. This method of providing fluoride is not feasible, however,where drinking water is obtained from small, private fluoride deficientsources (such as individual wells, etc.) rather than from fluoridated(naturally or fortified) common public sources. Further, the addition tocommon public sources is not always accepted or permitted, nor is itcompletely effective.

Topical applications of aqueous fluoride solutions by dentists or dentalhygienists provide an excellent measure of protection against dentalcaries. Various fluoride compounds have been employed for this purpose,including sodium fluoride and stannous fluoride. Likewise, dentifricesand mouthwash compositions comprising various fluoride compounds areknown to exhibit anti-cariogenic etfectiveness.

Although effective dental caries protection has been obtained throughthe use of the aforementioned fluoride compounds, occasional sideeifects have been experienced with certain of the known anticariogenicagents, particularly certain stannous ion containing salts. For example,a brownish pigmentation of certain carious lesions has been experiencedafter topical solutions of anticariogenic Patented Dec. 8, 1970 agentscontaining the stannous ion have been applied to the teeth when theteeth are not properly cleaned with a toothbrush following suchtreatment. Although the pigmentation of carious lesions is notnecessarily undesirable from a physiological standpoint, nevertheless,for aesthetic reasons, it would be desirable to provide an equallyefiective or superior anticariogenic agent that does not pigment thecarious enamel, but which has similar dental caries arrestmentpotential.

Moreover, the utility of certain of the prior art anticariogenic agentshas been limited by the extent of their solubility in an aqueous media.For example, sodium fluoride (NaF) is only soluble to the extent ofabout 4% in water. Solubility can, of course, limit the quantity ofanticariogenic ions provided by an agent that is available for reactionwith the tooth surface. The relative insolubility of certain of theprior art anticariogenic agents limits the value of the same for use inprophylactic paste compositions since the volume of water inprophylactic pastes is substantially limited.

Finally, certain of the known prior art anticariogenic agents have beenrelatively unstable in aqueous solutions. For example, stannous ions aresubject to oxidation and hydrolysis and, for that reason, stannouscontaining compositions must ordinarily be in freshly prepared form ormust be used in conjunction with complexing anions in order to obtainits optimal anticariogenic effect.

The anticariogenic effectiveness of the prior art agents has beenlimited by the aforementioned problems. Moreover, the utility of theseagents has been somewhat limited by the relative toxicity of theseagents. The percentage of these agents contained in oral compositionsmust be carefully maintained at a relatively low level to preventchronic toxicity of the agents in the body. Thus, maximum anticariogeniceifectiveness by the use of these agents cannot be obtained.

Accordingly, a primary object of the present invention is to provideoral compositions for dental caries prophylaxis comprising ananticariogenic agent exhibiting a high level of anticariogeniceffectiveness.

Another object of the present invention is to provide an anticariogenicagent of the character described that demonstrates substantial ionicstability.

Another object of the present invention is to provide an anticariogenicagent of the character described that is substantially non-toxic forhuman use.

Another object of the present invention is to provide an anticariogenicagent of the character described that does not pigment or discolor theoral hard tissues during or subsequent to use.

Another object of the present invention is to provide an anticariogenicagent of the character described that can be used at relatively highconcentrations relative to known anticariogenic fluoride-containingcompounds.

SUMMARY OF THE INVENTION In accordance with the present invention, ithas been found that new and more effective oral compositions for cariesprophylaxis may be obtained by utilizing a new composition of matter,indium fluorogermanate,

as an anticariogenic agent. Such oral compositions (which may take theform of dentifrices, prophylaxis pastes, topical solutions, andmouthwashes) comprise from about 0.01 to 50% by weight of the indiumfluorogermanate.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS The foregoing andother objects, advantages, and features of the present invention willhereinafter appear, and,

for the purposes of illustration, but not of limitation,

hereinafter described in detail.

Indium fluorogermanate, IN (GeF is a fine white crystalline powder. Thematerial is thermally stable to 170 C., at which time an as yetunidentified change occurs. The second material is stable to 600 C. atwhich temperature a second change occurs. At no time during the heatingdo identifiable oxides appear, though it is only reasonable to concludethat these are the end products.

PREPARATION AND PROPERTIES Indium fiuorogermanate may conveniently beprepared by co-precipitation or fusion methods. To prepare this compoundby co-precipitation, a total of 11.92 g. of ammonium fiuorogermanate,(NH GeF are completely dissolved in ml. of redistilled Water. In aseparate container 8.14 g. of indium chloride, InCl are dissolved in 20ml. of redistilled water. As the two solutions are mixed, a mildlyexothermic reaction occurs. The product, In (GeF is obtained byevaporation. The product is heated at 85 C. to volatilize the NH Clformed. In (GeF is formed in about 90% yield. The chemical equation forthe co-precipitation reaction is as follows:

3 GeF +2InCl I112 661 3 TABLE I.-ANALYSIS Theoretical, Element percentActual, percent In 29. 09 29. 08-39. 19 Ge 27. 59 27. 50-26. 94 F 43. 3243. 33-43. 87

Indium fluorogermanate is relatively soluble in Water at roomtemperature. Freshly prepared indium fluorogermanate is soluble in waterat room temperature at levels up to 33.1% by weight. The pH of aqueoussolutions of indium fluorogerrnanate is shown in Table II.

TABLE II Concentration (percent): pH 5.0 2.80

10.0 2.90 15.0 2.95 20.0 3.00 25.0 3.05 30.0 3.10 35.0 (super-saturatedsolution) 3.10

Indium fiuorogermanate, In (GeF has been characterized according to theconventional Hull-Debye- Scherrer X-ray diffraction powder technique inorder to produce a film record. Exposures were made using a standardX-ray diffraction camera (diameter 114.6 mm.) for four hours at 34 kv.and 18 ma. With a copper target and nickel filter. As is well known toone skilled in the art, the technique causes all chemical compounds todiffract X-rays according to a pattern specific for each compound. TheX-rays expose a film according to a specific pattern, which appears onthe film as characteristic lines, the interplanar spacing and therelative intensity of which may be measured in order to identify thecompound. For comparative purposes, corresponding values were obtainedfor (NH GeF InCl and NH Cl. The

4 pattern for In (GeF is distinctive and distinguishes this compoundfrom the other compounds evaluated.

ORAL COMPOSITIONS COMPRISING INDIUM FLUOROGERMANATE The compound of thisinvention may be applied to the teeth in simple aqueous solution form(as in a topical treatment) or in the form of an aqueous mouthwash;however, it is also well suited for use in other oral compositions forcaries prophylaxis which contain one or more ionically compatibleadjuvants. In general, oral compositions produced in accordance with thepresent invention comprise from about 0.01 to 50% by weight of indiumfluorogermanate.

Oral compoostions designed for relatively frequent use, such asdentifrices and mouthwashes, will contain lower levels of indiumfluorogermanate than compositions which are applied. less frequently(e.g., prophylaxis pastes and topical solutions). Thus, dentifricespreferably contain from about 0.1% up to about 1.0% by weight of indiumfluorogermanate, whereas prophylaxis pastes preferably comprise about 10to 30% indium fiuorogermanate by weight and aqueous topical solutionspreferably comprise about 5 to 40% indium fluorogermanate by weight.

The cleaning and polishing material in dentifrices of this invention cancomprise from about 20 to 95% by weight of the total composition.Preferably, toothpastes contain from 20 to cleaning and polishing agentby weight, and toothpowders contain from 60 to by weight. Examples ofsuitable cleaning and polishing agents suitable for use in a dentifriceinclude, without limitation, calcium pyrophosphate, Ca P O- calciumhydrogen phosphate dihydrate, CaI-IPO -2H O; anhydrous calcium hydrogenphosphate, CaHPO insoluble sodium metaphosphate, (NaPO calciumcarbonate, CaCO melamine formaldehyde resins (U.S. Pat. No. 3,070,-510); and preferably zirconium silicate and mixtures of zirconiumsilicate with other cleaning and polishing agents, as set forth anddescribed in applicants co-pending U.S. patent application, Ser. No.673,283, filed Oct. 6, 1967. Mixtures of these cleaning and polishingagents may also be used.

Toothpastes require a binder substance to impart desired textureproperties. Natural gum binders such as gum tragacanth, gum karaya, gumarabic, etc. and seaweed derivatives such as Irish moss, and alginates,and water soluble cellulose derivatives, such as hydroxyethyl celluloseand sodium carboxymethyl cellulose, can be us d for this purpose.Desirably those materials are employed which are not compatible with thefluoride ion. Binders which have no ionic groups, such as hydroxyethylcellulose, are especially preferred. Improvements in texture can also beattained by inculding an additional material such as colloidal magnesiumaluminum silicate.

Thickening agents in an amount of from 0.5% to 5.0% by weight can beused to form a satisfactory toothpaste.

Toothpaste conventionally contains sudsing agents. Suitable sudsingagents include, but are not limited to, Water-soluble alkyl sulfateshaving from 8 to 18 carbon atoms in the alkyl radical, such as sodiumlauryl sulfate, water-soluble salts of sulfonated monoglycerides, fattyacids having from 10 to 18 carbon atoms in the alkyl radical such assodium coconut monoglyceride sulfonate, salts of the fatty acid amidesof tuarines such as sodium-N- methyl palmitoyl tauride, and salts offatty esters of isethonic acid.

Sudsing agents can be used in the compositions of this invention in theamount from about 0.5 to about 5.0% by weight of the total composition.

It is also desirable to include some humectant material in toothpaste tokeep it from hardening. Materials commonly used for this purpose includeglycerine, sorbitol and other polyhydric alcohols. Humectants cancomprise up to 35% of the toothpaste composition.

Flavoring materials may be included in the toothpaste formulation,including small amounts of oils of wintergreen and peppermint, andsweetening agents such as saccharine, dextrose, and levulose.

An exemplary dentifrice formulation is given in the following example.

EXAMPLE I Constituent: Percent by weight Indium fluorogermanate 0.20Zirconium silicate 40.00 Sorbitol 20.00 Glycerine 10.00 Sodiumcarboxymethyl cellulose 1.08 Sodium coconut monoglyceride sulfonate 0.81Sodium lauryl sulfate 0.70 Flavor and minor ingredients 1.84 Distilledwater Balance EXAMPLE II Constituent: Percent by weight Indiumfluorogervmanate 20 Zirconium silicate 55 Liquids (water, binders, minoringredients) 25 Aqueous mouthwashes containing the indiumfluorogermanate salts constitute another preferred embodiment of thisinvention. An exemplary mouthwash composition is given in the followingexample.

EXAMPLE HI Constituent: Percent by weight Indium fluorogenmanate 0.07Ethyl alcohol (50% aqueous) 86.43 Flavoring 5.0 Sodium lauryl sulfate7.5 Acetic acid 1.0

ANTICARIOGENIC EFFECTIVENESS The anticariogenic effectiveness 'of indiumfluorogermanate may be demonstrated by the dental caries experience ofrats (standard experimental animals for anticariogenic studies). Theeffect of various dentifrice compositions in reducing the solubility ofdental enamel in acid is a reliable indicator of anticariogenicity.Enamel solubility characteristics of dental compositions can bedetermined by a number of tests well known in the art. The particulartest for reduction in tooth enamel solubility described herein comprisesa comparison of acid solubility of a given tooth before and aftertreatment with the given test composition. The said comparison isexpressed as ESR, that is, enamel solubility reduction.

The standard one-day test procedure to determine rat tooth ESR in vivois as follows. The teeth of a group of suitably selected test rats werebrushed three times in a four-hour period using various fluoride andnon-fluoride containing dentifrice compositions. One hour after the lastbrushing the animals were sacrificed by chloroform inhalation. Eachmandibular hemi jaw was removed, then the clinical crowns of each weredecalcified in 0.2 N (pH 4.0) sodium acetate buffer for twenty minutes.The decalcification solutions were then analyzed for phosphorus by acolorimetric method (Fisk and Subbarow, The Colorimetric Determinationof Phosphorus, J. Bio. Chem, 66:- 375, 1925). Phosphorus liberation ofthe teeth brushed with various dentifrice compositions was compared to anon-fluoride containing control, and the results of such comparison arereported as a percentage reduction of enamel solubility (i.e., ESR).

The effect of several fluoride-phosphate dentifrices upon enamelsolubility in rats was determined by tests utilizing the standardone-day procedure described above. A suitable number of test rats weredivided into a number of groups. Dentifrices were specially preparedutilizing various abrasive, fluoride, and phosphate ingredients. Theabrasive compounds used in these specially prepared dentifrices were acombination of ZrSiO -talc (1:3),

TABLE III Dentifrice constituents (percent by wt.)

E S R data, Fluoride mean percent Abraslve system Fluorlde conc-(percent) reduction Ca2P207- 1 Contains 18% tremolite as an impurity. 21:3 wt. mixture.

Additional tests have been performed utilizing the standard one-dayprocedure described above. All dentifrices utilized in this testcontained Ca P O- as the abrasive constituent. Dentifrices containing CaP O indium fluorogermanate. In '(GeF and Victamide were speciallyprepared. These dentifrices were compared to a non-fluoride,non-Victamide control dentifrice, and to a commercially availablestannous fluoride calcium pyrrphosphate dentifrice. The results of thesetests are reported in Table IV. These data show that indiumfluorogermanate possesses substantial anticariogenic effectiveness.

1 An ammonium salt of a condensation product of ammonia, NHs, andphosphorus pentoxide, P4010, as set forth and de scribed in U.S. PatentNo. 2,122,122 and commercially available under the Viotamide name fromthe Staufier Chemical Company,

7 TOXICITY In addition to exhibiting a high level of anticariogenicactivity, indium fluorogermanate exhibits a low toxicity, comparingquite favorably in this regard to other anticariogenic fluorides asshown by the following experimental studies.

The toxicity of indium fiuorogermanate has been determined in mice(standard experimental animals for this purpose. A total of 191 miceweighing between and g. each were given various concentrations of indiumfluorogermanate by means of a stomach tube. The results of this studyare reported in Table V, and these data indicate that the oral LD (theconcentration at which there is a 50% mortality rate) for indiumfluorogermanate in mice is approximately 85 mg. fluoride per kg. of bodyWeight. In comparison, the LD for NaF has been determined to beapproximately 36 mg. F/kg. Thus, the results indicate that the exemplaryindium fiuorogermanate salts are comparable or superior to knownfluorides.

TABLE V 2(GBF6)3 concentration No. animals (mg. F per kg. Initial numberdead in Percent body Weight) of animals 24 hours mortality Animalstudies further reveal that indium fluorogermanate when topicallyapplied, does not damage the gingival tissue of the test animals. Younganimals consisting of 100-200 g. rats or 100 g. hamsters were dividedinto appropriate groups. Test compositions containing In (GeF inconcentrations sufiicient to provide 1,000 ppm. fluoride in either anaqueous solution or dentifrice form were prepared. The solutions weretopically placed by applicators gently in the vestibule near themandibular molars for 30 seconds; and the dentifrices Were appliedeither by a toothbrush or cotton applicators directly to the mandibularmolar area for 30 seconds. The animals received treatments forpredetermined intervals, and were then sacrificed either one hour or 2.4hours following the final treatment. The oral tissue (mucous andsupporting structures) were surgically removed and prepared in the 8normal manner for histologic examination. Examination of the oral tissuerevealed that there was not any detectable change in the gingivaltissue.

While the present invention has been described herein with reference tocertain exemplary embodiments thereof, it should be understood thatvarious changes, modifications, and alterations may be eifected in thematerials utilized, in the proportions of materials, and in the mannerof formulation without departing from the spirit and the scope of thepresent invention, as defined in the appended claims.

I claim:

1. Oral compositions for dental caries prophylaxis comprising from about0.01% to 50% by Weight of indium fluorogermanate, In (GeF 2. An oralcomposition, as claimed in claim 1, wherein said composition is adentifrice and wherein the In (GeF is present at a level from about 0.1%to 1.0% by weight.

3. An oral composition, as claimed in claim 2 and further comprisingabout 20% to of at least one fluoride-compatible cleaning and polishingagent.

4. An oral composition, as claimed in claim 1, wherein said compositionis a prophylactic paste and wherein the In (GeF is present at a levelfrom about 5% to 30%.

5. An oral composition, as claimed in claim 4, and further comprisingabout 30% to of a fluoride-compatible cleaning and polishing agent.

6. An oral composition, as claimed in claim 1, wherein said compositionis an aqueous solution adapted for direct topical application to theteeth comprising about 5% to In (GeF 7. A method for increasing thedental caries resistance of teeth comprising the application thereto ofan oral composition for caries prophylaxis comprising about 0.01% to 50%of indium fluorogermanate, In (GeF 8. A method, as claimed in claim 7,wherein the composition is a dentifrice preparation comprising fromabout 0.1% to 1.0% of indium fluorogermanate, In (GeP 9. A method, asclaimed in claim 7, wherein the composition is a prophylactic pastecomprising about 5% to 30% indium fiuorogermanate, In (GeF 10. A method,as claimed in claim 7, wherein the composition is an aqueous solutioncomprising about 5% to about 40% indium fluorogermanate, In (GeF Noreferences cited.

RICHARD L. HUFF, Primary Examiner UNITED STATES PATENT OFFICECERTIFICATE OF CORRECTION Patent No. 3,546,335 Dated December 8, 1970Inventor() Joseph C. Muhler It: is certified that error appears in theabove-identified patent and that said Letters Patent are herebycorrected as shown below:

Column 3, line 42, "39. 19" should read -29. l9-;

Column 4, line 52, "not" should read --most--; and

Column 7, between lines 25 and 30, the sixth percentage "0. 7" in thecolumn entitled "Percent mortality should read -8. 7--.

Signed and sealed this 6th day of April 1971.

(SEAL) Attest:

EDNARD M.FLETCHER,JR. WILLIAM E. SGHUYLER, JR. Attesting OfficerCommissioner of Patents FORM PO-1050(10G9)

